ABSTRACT: The ability to predict the optimal therapy for an individual patient is a major unmet need in the treatment of cancer and other diseases. The majority of therapies in clinical cancer treatment, particularly cytotoxics as well as combinations of multiple drugs, have no reliable predictor of response. This uninformed therapy selection is highly inefficient and likely leads to reduced therapeutic success rates, increased side effects and excessive economic expenditures. I develop novel ?lab-in-a-patient? technology to probe, monitor, and eventually treat disease in real time within human tissue. A tiny, minimally invasive device will provide continuous output of information that reveals disease biology and informs treatment options. ?Lab-in-a-patient? technology has the potential to act as a micro-pathology laboratory by allowing the real-time measurement of response to multiple therapies or other chemical perturbagens simultaneously within the patient. We have achieved proof-of-concept for release of microdoses of a large number of distinct drugs or molecular ?sensors? in parallel into native tissue, with analysis of the effect for each such compound (Science Translational Medicine, 284ra57, 2015). We are augmenting this technology with miniaturized detection methods that enable optical in situ real-time monitoring of disease state and the effects of small molecules and biologics near each drug reservoir. This blend of high-throughput chemical perturbation and optical detection in a single instrument will, for the first time, enable diseased tissue to be monitored and functionally characterized in a continuous and noninvasive manner. It will thus provide unprecendented detail, precision and speed of analyzing response and resistance to therapeutics through live in situ readouts of signaling pathways, metabolites and other molecular markers. This approach may eventually push medicine away from trial-and-error treatments with longer-term macroscale endpoints and towards precision management of disease by probing, treating and monitoring locally at the microscale level. Use of the technology for local delivery of biological (non- therapeutic) probes into native tissue creates the capability for fundamental insights through direct stimulus-response measurements with real-time in situ monitoring, particularly in the areas of immunology, metabolism and cancer formation where the local tissue microenvironment plays a key role in the molecular processes underlying disease biology. In the fullness of time, these devices may enable individualized and real-time selection of optimal therapies and could facilitate rational design of more effective, personalized therapeutic regimens in numerous cancer indications. The proposed project spans continued technological and translational development that support eventual commercialization.